Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse

Abstract

Coordinated signalling between presynaptic terminals and their postsynaptic targets is essential for the development and function of central synapses. In addition to diffusible molecules, this bidirectional flow of information could involve direct interactions through cell-adhesion molecules. Here, we show that one class of cell-adhesion molecule, the integrins, are required for the functional maturation of hippocampal synapses in vitro. At immature synapses, a high probability of glutamate release (Pr) was correlated with the expression of postsynaptic NMDA (N-methyl-D-aspartate) receptors containing the NR2B subunit. The activity-dependent reduction in Pr and a switch in the subunit composition of synaptic NMDA receptors was prevented by chronic blockade with peptides containing the integrin-binding site Arg-Gly-Asp (RGD), or by a functional antibody against the beta3 integrin subunit. Active synapses, monitored by the uptake of antibodies against the intraluminal domain of synaptotagmin I, also had beta3 subunit immunoreactivity. Our results provide evidence that integrin-mediated signalling is essential for the orchestrated maturation of central excitatory synapses.

Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex

“…The observed deprivation-induced increase in the rate of neurotransmitter release is likely a compensatory mechanism to maintain synaptic drive in the absence of visually evoked activity. This increase in release is reminiscent of what has been observed in culture systems after manipulations that reduce presynaptic activity (Chavis and Westbrook, 2001) or postsynaptic excitability (Murthy et al, 2001). The enhanced neurotransmitter release at vertical intracortical connections after global sensory deprivation appears to be unique to adult sensory cortices, because global reductions in sensory activity in the developing somatosensory or visual cortices fail to modify neurotransmitter release (Finnerty and Connors, 2000;Philpot et al, 2001a).…”

Chronic Ethanol Exposure and Protracted Abstinence Alter NMDA Receptors in Central Amygdala

“…The sensitivity of NMDAR channels to ethanol is dependent on the NR2 subunit expressed: for example, NMDARs with NR1/2A and NR1/2B subunits are the most sensitive to ethanol (Allgaier, 2002;Lovinger, 1995;Mirshahi and Woodward, 1995). In contrast to mature hippocampus and cortex where NR1/NR2A subunits predominate (Chavis and Westbrook, 2001;Okabe et al, 1998;Scheetz and Constantine-Paton, 1994;Tovar and Westbrook, 1999), in the CeA, the NMDARs are composed mainly of NR1/NR2B subunits and with little or no developmental change in subunit composition (Lopez de Armentia and Sah, 2003).…”

Variation in ITGB3 is associated with whole-blood serotonin level and autism susceptibility

“…First, it has been hypothesized that high peripheral serotonin levels might influence central serotonin by feedback mechanisms before formation of the blood -brain barrier. 41 Second, integrins, including b3, have been shown to be critical to synapse maturation in the hippocampus, 42 suggesting not only expression but also vital function in the developing brain.…”